WO2023089906A1 - Agent d'inhibition de fuite pour substance d'injection locale, substance d'injection locale le contenant, et procédé de production d'une substance d'injection locale - Google Patents

Agent d'inhibition de fuite pour substance d'injection locale, substance d'injection locale le contenant, et procédé de production d'une substance d'injection locale Download PDF

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Publication number
WO2023089906A1
WO2023089906A1 PCT/JP2022/032793 JP2022032793W WO2023089906A1 WO 2023089906 A1 WO2023089906 A1 WO 2023089906A1 JP 2022032793 W JP2022032793 W JP 2022032793W WO 2023089906 A1 WO2023089906 A1 WO 2023089906A1
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Prior art keywords
local injection
injection
leakage
mass
sample
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PCT/JP2022/032793
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English (en)
Japanese (ja)
Inventor
知希 小谷
陽介 平岡
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新田ゼラチン株式会社
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Application filed by 新田ゼラチン株式会社 filed Critical 新田ゼラチン株式会社
Priority to CA3220517A priority Critical patent/CA3220517A1/fr
Priority to KR1020247003686A priority patent/KR20240095404A/ko
Priority to CN202280067824.3A priority patent/CN118119407A/zh
Publication of WO2023089906A1 publication Critical patent/WO2023089906A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present invention relates to a leakage inhibitor for local injections, a local injection containing the same, and a method for producing a local injection.
  • Patent Document 1 Japanese Patent Application Laid-Open Nos. 2007-001989 (Patent Document 1) and 2001-192336 (Patent Document 2) disclose protuberance of the mucous membrane by extending the local residence time of the active ingredient in order to contribute to resection of the affected area.
  • an injectable formulation that induces In order to extend the local residence time of the active ingredient, at least it is required to reduce the leakage of the injection from the affected area, that is, to suppress the leakage of the injection.
  • Patent Document 1 states that it is effective to set the viscosity of the aqueous solution containing hyaluronic acid, which is the active ingredient in the injection, to 40 mPa ⁇ s or more in order to suppress leakage of the injection.
  • Patent Document 2 teaches the use of 0.2 to 1.0% by mass of hyaluronic acid having a weight average molecular weight of 600,000 to 1,200,000.
  • the present invention provides a leakage inhibitor for local injections that can suppress leakage of injections and allows active ingredients and the like to stay at the target site, local injections containing the same, and local injections. It aims at providing the manufacturing method of an injection.
  • the present inventors have made intensive studies to achieve the above objectives and arrived at the present invention.
  • First, the present inventors have noticed that the viscosity is maintained at a relatively low level even when a gelatin hydrolyzate having a predetermined weight-average molecular weight is contained at a high concentration in an aqueous solvent.
  • the leakage inhibitor for topical injection according to the present invention contains a gelatin hydrolyzate having a weight-average molecular weight of 5000 or less.
  • the viscosity at 25° C. of the first solution with a substance concentration of 40% by mass is 20 mPa ⁇ s or less.
  • the leakage inhibitor is composed of the gelatin hydrolyzate.
  • the above-mentioned leakage inhibitor is for a local injection to be filled in a syringe equipped with a needle having an outer diameter of 23G or more and 37G or less.
  • the above-mentioned leakage inhibitor is for a local injection to be filled in a syringe equipped with a needle having an outer diameter of 23G or more and 27G or less.
  • the local injection according to the present invention contains the above-described leakage inhibitor.
  • the local injection preferably contains the leakage inhibitor in an amount of 5% by mass or more and 40% by mass or less, and the viscosity of the local injection at 25°C is preferably 2 mPa ⁇ s or more and 20 mPa ⁇ s or less.
  • the local injection preferably contains the leakage inhibitor in an amount of 5% by mass or more and 40% by mass or less, and the viscosity of the local injection at 25°C is preferably 2 mPa ⁇ s or more and 10 mPa ⁇ s or less.
  • the local injection preferably contains the leakage inhibitor in an amount of 5% by mass or more and 40% by mass or less, and the viscosity of the local injection at 25°C is preferably 8 mPa ⁇ s or more and 20 mPa ⁇ s or less.
  • a method for producing a local injection according to the present invention is a method for producing the above local injection, comprising: preparing the leakage inhibitor, an aqueous solvent, and an active ingredient; and a step of obtaining a local injection by mixing the components with the aqueous solvent at 1°C or higher and 30°C or lower.
  • the step of obtaining the local injection includes mixing the leakage inhibitor with the aqueous solvent to obtain a first injection precursor, and then mixing the active ingredient with the first injection precursor. or by mixing the active ingredient with the aqueous solvent to obtain a second injection precursor, and then mixing the leakage inhibitor with the second injection precursor. It is preferable to select either the step of obtaining a topical injection or the step of obtaining a topical injection by simultaneously mixing the leakage inhibitor and the active ingredient in the aqueous solvent.
  • a leakage inhibitor for local injections capable of suppressing leakage of an injection and allowing an active ingredient or the like to stay at a target site, a local injection containing the same, and a local injection.
  • a manufacturing method can be provided.
  • this embodiment the embodiment according to the present invention (hereinafter also referred to as “this embodiment”) will be described in more detail.
  • the notation of the format “A to B” means the upper and lower limits of the range (that is, A to B or less), and when there is no unit description in A and only a unit is described in B , the units of A and B are the same.
  • the term “gelatin” may be used when referring to the substance name, gelatin gel, and gelatin solution, respectively.
  • gelatin hydrolyzate may also be used when referring to a gelatin hydrolyzate solution, as in the case of the gelatin described above.
  • the term "local injection” refers to all injection methods, excluding injections in which a needle is inserted into a blood vessel such as intravenous injection. It means injection around it, injection into soft tissue, injection into joints such as the knee or the facet joints of the spine, and the like.
  • the gelatin hydrolyzate is dissolved in phosphate-buffered saline and the concentration of the gelatin hydrolyzate is 40% by mass. is dissolved in phosphate-buffered physiological saline, and liquids in which the gelatin hydrolyzate is dispersed without being slightly dissolved.
  • the "first solution” may be a liquid in which it is dispersed without being dissolved.
  • the leakage suppressor for local injection contains a gelatin hydrolyzate having a weight average molecular weight of 5000 or less. Furthermore, the gelatin hydrolyzate was dissolved in phosphate buffered saline (hereinafter also referred to as "PBS buffer"), and the concentration of the gelatin hydrolyzate was set to 40% by mass. , 20 mPa ⁇ s or less. It is preferable that the leakage suppressor comprises a gelatin hydrolyzate. By having such characteristics, the leakage suppressing agent can suppress leakage of the local injection from the target site, thereby allowing the local injection to stay at the target site. Furthermore, even when the leakage inhibitor is contained in an aqueous solvent at a high concentration, the viscosity can be maintained at a relatively low level. Become.
  • the leakage inhibitor contains a gelatin hydrolyzate having a weight average molecular weight of 5000 or less as described above.
  • gelatin hydrolyzate refers to a peptide aggregate (hydrolyzate) obtained by hydrolyzing both or either one of gelatin and collagen. That is, “gelatin hydrolyzate” means the equivalent of an assembly of peptides commonly referred to as collagen peptides or collagen hydrolysates.
  • the gelatin hydrolyzate contained in the leakage inhibitor has a weight average molecular weight (5000 or less) as described above.
  • the gelatin hydrolyzate means an assembly of peptides as described above, it has the same characteristics as collagen and gelatin, such as having a primary structure in which glycine is repeated every three residues in the amino acid sequence that constitutes the peptide chain. have.
  • gelatin means a polypeptide in which the triple helical structure of collagen is unwound by heat denaturation, acid denaturation, etc., chemical modifications thereof, and pharmaceutically acceptable salts thereof.
  • collagen derived from at least one selected from the group consisting of Groups 1 to 6 below is subjected to conventionally known treatments such as degreasing treatment, decalcification treatment, acid or alkali treatment, and hot water extraction treatment. It can be obtained by applying the treatment of Gelatin may be a polypeptide obtained by fermentation using microorganisms, a recombinant polypeptide obtained by chemical synthesis or genetic recombination, or a synthesized polypeptide.
  • collagen refers to proteins derived from the extracellular matrix in the skin of vertebrates, which are classified into Groups 1 to 6 below.
  • Collagen has a right-handed helical structure consisting of three peptide chains, and the amino acid residues constituting the peptide chain have a primary structure in which glycine residues are repeated every three residues (so-called collagen-like sequence). have.
  • Group 1 Group consisting of hide, skin, bone, cartilage and tendon of cattle
  • Group 2 Group consisting of hide, skin, bone, cartilage and tendon of pig
  • Group 3 Hide, skin, bone, cartilage and tendon of sheep
  • Group 4 Group consisting of chicken skin, skin, bones, cartilage and tendons
  • Group 5 Group consisting of ostrich skin, skin, bones, cartilage and tendons
  • Group 6 Fish bones, skin and scales The group consisting of
  • the "chemically modified form" of the above polypeptide (gelatin) means a polypeptide in which the amino group, carboxyl group, hydroxy group, thiol group, etc. of the amino acid residues constituting gelatin are chemically modified.
  • Chemically modified gelatin can change its solubility in water, isoelectric point, and the like. Specifically, chemical modifications such as O-acetylation can be carried out on the hydroxy groups of hydroxyproline residues in gelatin. Chemical modifications such as esterification and amidation can be performed on the ⁇ -carboxyl group of glycine residues in gelatin.
  • Chemical modification of the hydroxy group of a hydroxyproline residue can be carried out, for example, by O-acetylation, such as by reacting acetic anhydride in an aqueous or non-aqueous solvent.
  • O-acetylation such as by reacting acetic anhydride in an aqueous or non-aqueous solvent.
  • esterification can be carried out, such as by bubbling dry hydrogen chloride gas after suspension in methanol.
  • amidation can be carried out by the action of carbodiimide or the like.
  • the above-mentioned “derivatives" of the polypeptide (gelatin) include gelatin derivatives obtained by introducing functional groups into gelatin, copolymers of gelatin with lactic acid, glycolic acid, etc., and copolymers of gelatin with polyethylene glycol and propylene glycol. etc. may be included.
  • gelatin derivatives include derivatives obtained by introducing functional groups such as guanidyl groups, thiol groups, amino groups, carboxyl groups, sulfate groups, phosphoric acid groups, alkyl groups, acyl groups, phenyl groups, and benzyl groups into gelatin. be able to.
  • “Pharmaceutically acceptable salt” of the above polypeptide (gelatin) means a salt that is pharmaceutically acceptable and has the desired activity (eg, gelling ability) of the original polypeptide (gelatin).
  • Pharmaceutically acceptable salts include inorganic acid salts such as hydrochlorides, sulfates, phosphates and hydrobromides, acetates, methanesulfonates, benzenesulfonates, p-toluenesulfonates. , organic acid salts such as succinate, oxalate, fumarate and maleate; inorganic base salts such as sodium, potassium and calcium salts; and organic base salts such as triethylammonium salt. can.
  • a specific peptide in gelatin can be converted into a pharmaceutically acceptable salt according to a conventional method.
  • gelatin is a polypeptide derived from collagen that many organisms possess, it has excellent biocompatibility. Therefore, the gelatin hydrolyzate obtained by hydrolyzing the above collagen and gelatin also has excellent biocompatibility and is suitable as a component (leakage inhibitor) contained in local injections for medical use.
  • the term "sol” means a dispersion system comprising a dispersoid and a dispersion medium, in which the dispersion medium is liquid.
  • “Gel” means a state in which the dispersoids form a crosslinked structure in a dispersion system composed of dispersoids and a dispersion medium, and the dispersion system as a whole loses fluidity.
  • a gelatin hydrolyzate can be obtained by hydrolyzing either or both gelatin and collagen as described above.
  • “hydrolysis” includes hydrolysis using acids, hydrolysis using bases, hydrolysis using enzymes, and hydrolysis using heat. From the viewpoint of preventing contamination with impurities, the gelatin hydrolyzate is preferably obtained by hydrolysis using heat.
  • the enzyme include collagenase, thiol protease, serine protease, acid protease, alkaline protease, metalloprotease, and the like. The above enzymes can be used singly or in combination.
  • Examples of the thiol protease include plant-derived chymopapain, papain, bromelain, ficin, animal-derived cathepsin, calcium-dependent protease, and the like.
  • Examples of the serine protease include trypsin, cathepsin D, and the like.
  • Examples of the acid protease include pepsin and chymotrypsin.
  • Non-pathogenic microorganisms from which the above enzymes are derived include Bacillus iicheniforms, Bacillus subtillis, Aspergillus oryzae, Streptomyces, Bacillus amyloliquefaciens, and the like.
  • an enzyme derived from one of the above-described non-pathogenic microorganisms may be used, or a plurality of types of enzymes derived from the above-described non-pathogenic microorganisms may be used in combination.
  • a conventionally known method may be used as a specific method for enzymatic treatment.
  • the gelatin hydrolyzate is preferably liquid or powder.
  • a topical injection can be easily prepared from the leakage inhibitor, the active ingredient described below, and an aqueous solvent.
  • the gelatin hydrolyzate is in the form of powder, the above-mentioned leakage inhibitor is dissolved or dispersed in an aqueous solvent to prepare a solvent for injection, and an active ingredient is added to the solvent to easily prepare a local injection. can be done.
  • a gelatin hydrolyzate can be obtained as a liquid by hydrolyzing both or either one of gelatin and collagen by the method described above, followed by purification. Furthermore, it is possible to obtain a powder by heat-drying or freeze-drying the liquid by a known means.
  • the gelatin hydrolyzate has a weight average molecular weight of 5,000 or less.
  • the gelatin hydrolyzate preferably has a weight average molecular weight of 3000 or more and 5000 or less.
  • the leakage inhibitor maintains a relatively low viscosity even when it is contained in an aqueous solvent at a high concentration, so that when applied as a local injection, high back pressure is not required. Therefore, it is possible to achieve the effect of suppressing leakage at the target site.
  • the weight average molecular weight of the gelatin hydrolyzate is 5000 or less, the gelatin molecules are decomposed into moderate lengths, and even at high concentrations, the molecules are less likely to entangle. , it is presumed that the viscosity can be maintained at a relatively low level even when it is contained in an aqueous solvent at a high concentration. This makes it possible to easily prepare a local injection with a leakage-suppressing effect.
  • the viscosity may increase beyond the allowable range.
  • the lower limit of the weight-average molecular weight of the gelatin hydrolyzate is not particularly limited, for example, the weight-average molecular weight of the gelatin hydrolyzate is preferably 500 or more.
  • the weight average molecular weight of the gelatin hydrolyzate can be determined by performing gel filtration chromatography under the following measurement conditions.
  • Equipment high performance liquid chromatography (HPLC) (manufactured by Tosoh Corporation) Column: TSKGel® G2000SW XL Column temperature: 30°C Eluent: 40 wt% acetonitrile (containing 0.05 wt% TFA) Flow rate: 0.5mL/min Injection volume: 10 ⁇ L Detection: UV220nm
  • Molecular weight marker Use the following three types Aprotinin Mw: 6512 Bacitracin Mw: 1423 Gly-Gly-Tyr-Arg Mw: 451.
  • the leakage suppressor containing the gelatin hydrolyzate was added to about 100 ml of distilled water, stirred, and then filtered using a 0.2 ⁇ m filter to reduce the weight average molecular weight.
  • a sample to be measured (object to be measured) is prepared.
  • the weight-average molecular weight of the gelatin hydrolyzate can be obtained by measuring the substance to be measured under the gel filtration chromatography conditions described above.
  • the gelatin hydrolyzate preferably has an isoelectric point of pH 4.0 or higher and 5.5 or lower, more preferably pH 4.0 or higher and 4.7 or lower.
  • the hydrolyzate of gelatin is preferably a hydrolyzate of alkali-treated gelatin having an isoelectric point of about pH 4.8 to 5.5. That is, the gelatin hydrolyzate is preferably a hydrolyzate of alkali-treated gelatin.
  • gelatin obtained by treating collagen with an inorganic acid is called acid-treated gelatin
  • gelatin obtained by treating collagen with an inorganic base is called alkali-treated gelatin.
  • Alkali-treated gelatin can be specifically obtained by treating collagen with an inorganic base such as sodium hydroxide, calcium hydroxide or potassium hydroxide.
  • the leakage inhibitor for local injections may be applied to local injections containing components such as viruses, viral DNA or RNA fragments, or viral proteins, as described later.
  • the gelatin hydrolyzate contained in the leakage inhibitor exhibits the pH of the isoelectric point as described above
  • the gelatin hydrolyzate in the local injection suppresses aggregation of the above-mentioned components of the virus. It is possible to suppress the decrease in virus titer.
  • the gelatin hydrolyzate exhibiting the pH of the isoelectric point possessed by alkali-treated gelatin exhibits a negative charge as a whole.
  • the gelatin hydrolyzate can bind to the virus by exhibiting a weak electrostatic interaction with each component in the virus at the positively charged site.
  • the gelatin hydrolyzate repels each other with the virus and other peptide chains that make up the gelatin hydrolyzate at the negatively charged sites. From the above, it is presumed that the gelatin hydrolyzate can stabilize the virus in the topical injection while suppressing virus aggregation.
  • the pH of the isoelectric point of the gelatin hydrolyzate can be obtained by measuring the pH of the isoelectric point of either or both of gelatin and collagen, which are raw materials of the gelatin hydrolyzate, using a conventionally known method. However, it is preferable to use the following method for measuring the isoelectric point using the zeta potential as an index, since the isoelectric point value can be obtained more accurately. First, a gelatin hydrolyzate to be measured is dissolved in an acetate buffer (pH 4.0 to 5.5) to obtain a 0.4 w/v % solution to be measured.
  • the solution to be measured is filtered through a 0.22 ⁇ m filter (manufactured by Merck), and then 0.8 mL of the solution to be measured is filled into a capillary cell while preventing air bubbles from entering.
  • the capillary cell filled with the solution to be measured is set in a zeta potential measuring device (manufactured by Malvern Panalytical) to measure the zeta potential at each pH at 25°C.
  • the pH value at which the zeta potential becomes 0 can be obtained as the isoelectric point of the solution to be measured (the gelatin hydrolyzate to be measured).
  • the concentration of the gelatin hydrolyzate in the leakage inhibitor is not particularly limited, but from the viewpoint of facilitating the preparation of local injections, it is preferably 25% by mass or more and 100% by mass or less. If the concentration of the gelatin hydrolyzate in the leakage inhibitor is less than 25% by weight, a large amount of the leakage inhibitor is required to exhibit the leakage inhibitory effect when preparing a local injection, which is difficult. . More preferably, the concentration of the gelatin hydrolyzate in the leakage inhibitor is 50% by mass or more and 100% by mass or less, and the concentration of the gelatin hydrolyzate in the leakage inhibitor is 100% by mass. It is also preferred that the leakage control agent consists of a gelatin hydrolyzate.
  • ingredients other than the gelatin hydrolyzate as the leakage inhibitor include ingredients other than the gelatin hydrolyzate derived from gelatin or collagen, diluents, binders (syrup, gum arabic, sorbitol, tragacanth, polyvinylpyrrolidone), excipients (lactose, sucrose, corn starch, potassium phosphate, sorbitol, glycine), lubricants (magnesium stearate, talc, polyethylene glycol, silica), disintegrant (potato starch) and wetting agent. agent (sodium lauryl sulfate) and the like.
  • the concentration of the gelatin hydrolyzate in the leakage inhibitor can be measured by a known method such as hydroxyproline determination.
  • the gelatin hydrolyzate is dissolved in PBS buffer, and the gelatin hydrolyzate concentration is 40% by mass.
  • the first solution has a viscosity at 25° C. of , 20 mPa ⁇ s or less. That is, the first solution is an aqueous solution in which the gelatin hydrolyzate contained in the leakage inhibitor is dissolved in PBS buffer and the concentration of the gelatin hydrolyzate is 40% by mass, or the concentration of the gelatin hydrolyzate is 40% by mass. %, and the gelatin hydrolyzate is slightly dispersed without being dissolved. Furthermore, the viscosity of the first solution at 25° C.
  • the leakage inhibitor exhibits a relatively low viscosity even when the aqueous solvent contains the gelatin hydrolyzate at a high concentration.
  • the local injection containing the above leakage inhibitor can exhibit the effect of suppressing leakage from the target site even though high back pressure is not required at the time of injection.
  • the outer diameter of the injection needle applied to the syringe filled with the local injection is By appropriately selecting, it is possible to exhibit a more effective leakage control effect.
  • the lower limit of the viscosity of the first solution at 25° C. should not be particularly limited, but from the viewpoint of further exhibiting the effect of suppressing leakage from the target site of the local injection containing the above-described leakage inhibitor, It is preferably 5 mPa ⁇ s or more.
  • gelatin hydrolysates with a weight-average molecular weight of 5,000 or less have a fairly wide molecular weight distribution, and gelatin hydrolysates containing more than a certain amount of high-molecular components tend to entangle with each other, resulting in an increase in viscosity. is presumed. Therefore, the viscosity at 25° C. of the first solution obtained by dissolving such a gelatin hydrolyzate in a PBS buffer to a concentration of 40% by mass may exceed 20 mPa ⁇ s.
  • the viscosity of the first solution is measured at 25° C. with a rheometer (trade name (product number): “MCE302”, Anton Paar Japan Co., Ltd., cone plate R25, 1°, shear rate 200 s ⁇ 1 ). can be done.
  • a rheometer trade name (product number): “MCE302”, Anton Paar Japan Co., Ltd., cone plate R25, 1°, shear rate 200 s ⁇ 1 .
  • the leakage inhibitor for local injections is for local injections.
  • the leakage inhibitor is preferably for local injection filled in a syringe equipped with a needle having an outer diameter of 23G or more and 37G or less. It is also preferable that the above-mentioned leakage inhibitor is for a local injection to be filled in a syringe equipped with a needle having an outer diameter of 23G or more and 27G or less.
  • local injection includes, for example, intradermal injection, subcutaneous injection, intramuscular injection, injection into a nerve or its surroundings, injection into soft tissue, injection into a joint such as a knee or a facet joint of the spine, and the like.
  • the above-mentioned leakage inhibitor has hitherto unknown properties of gelatin hydrolysates, i.e., unknown properties such as intradermal, subcutaneous, intramuscular, nerve or its surroundings, soft tissues, and facet joints of the knee and spine. It has the effect of suppressing leakage of the injection from the target site such as the inside of the joint and allowing it to remain at the target site. Therefore, the leakage inhibitor can be an effective new use for gelatin hydrolysates.
  • an injection needle having an outer diameter of 23G or more and 37G or less specifically refers to an injection needle having an outer diameter of 0.08 ⁇ 0.02 mm to 0.64 ⁇ 0.02 mm. That is, the 23G needle has an outer diameter of 0.64 ⁇ 0.02 mm, the 24G needle has an outer diameter of 0.56 ⁇ 0.02 mm, and the 25G needle has an outer diameter of 0.51 ⁇ 0.02 mm. , the 26G injection needle has an outer diameter of 0.46 ⁇ 0.02 mm, and the 27G injection needle has an outer diameter of 0.41 ⁇ 0.02 mm.
  • the 28G needle has an outer diameter of 0.36 ⁇ 0.02 mm
  • the 29G needle has an outer diameter of 0.33 ⁇ 0.02 mm
  • the 30G needle has an outer diameter of 0.31 ⁇ 0.02 mm
  • the 31G injection needle has an outer diameter of 0.27 ⁇ 0.02 mm
  • the 32G injection needle has an outer diameter of 0.23 ⁇ 0.02 mm
  • the 33G injection needle has an outer diameter of 0.20 ⁇ 0.02 mm
  • the 35G injection needle has an outer diameter of 0.15 ⁇ 0.02 mm
  • the 36G injection needle has an outer diameter of 0.10 ⁇ 0.02 mm
  • 37G injection needles each have an outer diameter of 0.08 ⁇ 0.02 mm.
  • the leakage inhibitor suppresses the leakage of the active ingredient in the local injection from the target site in various applications in which a syringe having an injection needle having an outer diameter of 23G or more and 37G or less is applied. It can stay in place.
  • the above-mentioned leakage suppressor is particularly useful for intratumoral administration and general intramuscular injection to which a syringe with a needle with an outer diameter of 23G is applied, and a syringe with a needle with an outer diameter of 27G. It is suitable for cell transplantation into soft tissue to which is applied and general intradermal injection.
  • the above leakage inhibitor can also be applied to ultra-fine injection needles (for example, 37G, outer diameter 0.08 mm, inner diameter 0.05 mm) used in ophthalmology.
  • the local injection contains the leakage inhibitor.
  • the local injection can prevent the active ingredient from leaking out of the target site and allow the active ingredient to remain at the target site.
  • the local injection can contain active ingredients such as drugs, viruses, cells, or other physiologically active substances, and an aqueous solvent that serves as a medium for dissolving or dispersing the leakage inhibitor. .
  • the local injection includes, as an active ingredient, a drug, a virus, a fragment of viral DNA or RNA, each component such as a viral protein (hereinafter also referred to as "virus etc.”), cells, or other physiological substances. It can contain active substances.
  • a drug is applicable as an injection, it may be a drug containing an inorganic compound, a drug containing a compound that can be produced by an organic synthesis reaction, or a compound extracted from a natural product or the like.
  • the agent may be a derivative of the active molecule, a precursor of the molecule, or a salt of the molecule.
  • derivative refers to modifying the structure of a part of the molecule by introducing a functional group into the molecule or performing an oxidation-reduction reaction on the molecule.
  • a "precursor" of a molecule means a substance that precedes the biosynthetic or synthetic production of the molecule.
  • a “salt” of a molecule means a salt formed by treatment with acids or bases while retaining the activity of the molecule itself.
  • enveloped DNA viruses non-enveloped DNA viruses, enveloped RNA viruses, and non-enveloped RNA viruses can be used as the above-mentioned local injection.
  • each component such as DNA or RNA fragments of these viruses or viral proteins can also be used in the local injections.
  • the gelatin hydrolyzate contained in the topical injection can suppress the aggregation of the virus, so it can suppress the decrease in the virus titer, and thus the refrigeration temperature (2 to 8 ° C.) and at room temperature around 25° C., the stability of topical injections containing the virus or components of the virus can be improved.
  • physiologically active substances examples include various cells (including both stem cells and differentiated cells), growth factors, differentiation factors, hormones, chemokines, cytokines, cell adhesion molecules, chemotactic factors, enzymes, enzyme inhibitors, Coenzymes (vitamins), minerals, fats, lipids, stabilizers and preservatives and the like can be mentioned. Any of these physiologically active substances can be used in the local injection.
  • the local injection according to this embodiment can contain an aqueous solvent as described above.
  • aqueous solvent refers to a medium that dissolves or disperses the leakage inhibitor, and means a medium that can contain components other than water, such as amino acids, sugars, and salts with buffering action, which will be described later.
  • the aqueous solvent may be a buffer solution containing a buffering salt.
  • the aqueous solvent may be a GTS buffer.
  • Aqueous solvents can improve the stability of topical injections.
  • salts having a buffering action examples include sodium phosphate, potassium phosphate, calcium phosphate, magnesium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, calcium hydrogen phosphate, magnesium hydrogen phosphate, sodium chloride, potassium chloride, and the like. can do.
  • the aqueous solvent may contain one of the above salts having a buffering action, or may contain two or more of them in combination.
  • Examples of aqueous solvents containing salts having buffering action include the GTS buffer, PBS buffer, Tris buffer, HEPES buffer, citrate buffer, and the like.
  • the aqueous solvent preferably contains at least one amino acid selected from the group consisting of methionine, arginine, tryptophan, glutamine and glutamic acid.
  • the aqueous solvent may contain one type of amino acid selected from these groups alone, or may contain two or more types in combination. More preferably, the aqueous solvent contains either or both of methionine and arginine amino acids. The local injection can contribute to improved stability even when it contains an amino acid.
  • the aqueous solvent preferably contains at least one sugar selected from the group consisting of sucrose, lactose, sorbitol, inositol, trehalose, mannitol, maltitol, xylitol, erythritol and glycerol.
  • the aqueous solvent may contain one type of saccharide selected from these groups alone, or may contain two or more types in combination. More preferably, the aqueous solvent contains at least one of sucrose, lactose and sorbitol. The local injection can contribute to improved stability even when it contains saccharides.
  • sugars include not only organic compounds generally classified as sugars, but also organic compounds classified as sugar alcohols.
  • Organic compounds classified as sugar alcohols in the above group of sugars are the above sorbitol, mannitol, maltitol, xylitol, erythritol and glycerol.
  • the local injection preferably contains 5% by mass or more and 40% by mass or less of the leakage inhibitor.
  • the viscosity of the local injection at 25° C. is preferably 2 mPa ⁇ s or more and 20 mPa ⁇ s or less. If the concentration of the leakage suppressing agent contained in the local injection is less than 5% by mass, it becomes difficult to obtain a predetermined viscosity, making it difficult to achieve the desired leakage suppressing effect. If the concentration of the leakage inhibitor contained in the local injection exceeds 40% by mass, the viscosity may increase beyond the allowable range.
  • the concentration of the leakage inhibitor contained in the local injection is more preferably 10% by mass or more and 40% by mass or less, even more preferably 20% by mass or more and 40% by mass or less, and more than 20% by mass. It is even more preferable that it is less than % by mass.
  • concentration of the leakage inhibitor in the topical injection is measured using a known method such as hydroxyproline quantification by regarding the leakage inhibitor as substantially consisting of gelatin hydrolyzate. can be done.
  • the local injection contains 5% by mass or more and 40% by mass or less of the leakage inhibitor, and the viscosity of the local injection at 25°C is 2 mPa ⁇ s or more and 10 mPa ⁇ s or less.
  • the local injection more preferably contains 10% by mass or more and 40% by mass or less of the leakage inhibitor when filled in a syringe equipped with an injection needle having an outer diameter of 27G.
  • the local injection preferably contains 5% by mass or more and 40% by mass or less of the leakage inhibitor, and the viscosity of the local injection at 25°C is 8 mPa ⁇ s or more and 20 mPa ⁇ s or less.
  • the leakage inhibitor be contained in an amount of 10% by mass or more and 40% by mass or less.
  • the local injection according to this embodiment can contain the leakage inhibitor, the active ingredient, and the aqueous solvent as described above, and in that case, the active ingredient can be retained at the target site without leakage. can be done.
  • the local injection contains a virus or the like as an active ingredient
  • the local injection can suppress aggregation of the virus or the like in the local injection, thereby suppressing a decrease in the virus titer. ⁇ 8°C) and room temperature around 25°C can improve the stability of topical injections.
  • local injections are expected to be suitable for applications such as cell therapy because they are excellent in cell retention and cell ejection as described later.
  • the local injection according to this embodiment can preferably be obtained by the following method. That is, the method for producing a local injection according to the present embodiment includes a step of preparing the leakage inhibitor, an aqueous solvent, and an active ingredient (first step), and adding the leakage inhibitor and the active ingredient to the aqueous solvent. It is preferable to include a step of obtaining a local injection (second step) by mixing at a temperature of 30° C. or higher.
  • the above-mentioned "active ingredient” and "aqueous solvent” have the same meanings as the "active ingredient” and "aqueous solvent” described in the above item [Local Injection], and redundant description will not be repeated.
  • the first step is a step of preparing the leakage inhibitor, the aqueous solvent, and the active ingredient.
  • the gelatin hydrolyzate contained in the leakage inhibitor can be obtained by hydrolyzing both or either one of gelatin and collagen as described above so that the weight average molecular weight is 5000 or less.
  • the leakage inhibitor can be prepared by mixing a gelatin hydrolyzate and other components at a mass ratio such that the concentration of the gelatin hydrolyzate is 25% by mass or more and 100% by mass or less.
  • a conventionally known method can be used as a specific method for mixing the gelatin hydrolyzate and other ingredients.
  • the aqueous solvent when the aqueous solvent contains a salt having a buffering action, it can be prepared by a conventionally known method such as adding the salt to deionized water so as to obtain a predetermined concentration.
  • Active ingredients can be prepared by conventionally known methods for preparing drugs, viruses, etc., or other physiologically active substances.
  • the second step is to obtain a local injection by mixing the leakage inhibitor and the active ingredient with the aqueous solvent at 1°C or higher and 30°C or lower.
  • the leakage inhibitor and the active ingredient can be mixed with an aqueous solvent at room temperature of 1°C or higher and 30°C or lower to prepare a local injection, so that a local injection can be obtained very easily. can be done.
  • the temperature at which the leakage inhibitor, active ingredient and aqueous solvent are mixed is more preferably 15° C. or higher and 25° C. or lower, more preferably 20° C. or higher and 25° C. or lower, from the viewpoint of easily obtaining a local injection. It is even more preferable to have
  • the second step (the step of obtaining a local injection)
  • the active ingredient is added to the first injection precursor.
  • step 2a or after obtaining a second injection precursor by mixing the active ingredient with the aqueous solvent
  • step 2b the second A step of obtaining a local injection by mixing the leakage inhibitor with the injection precursor
  • step 2c step it is preferable to be any of the steps of obtaining a local injection.
  • step 2a before mixing the active ingredient, the leakage inhibitor and the aqueous solvent are mixed to obtain the first injection precursor. Therefore, for example, when a compound that hydrolyzes quickly (for example, a compound having a structure such as an ester, an amide, or a lactam) is used as an active ingredient, if step 2a is used as the step for obtaining a local injection, the second step can be performed immediately before the local injection.
  • a compound that hydrolyzes quickly for example, a compound having a structure such as an ester, an amide, or a lactam
  • Step 2b before mixing the leakage inhibitor, the active ingredient and the aqueous solvent are mixed to obtain the second injection precursor. Therefore, for example, when the active ingredient is a compound or the like whose action is likely to be affected by a change in viscosity due to a leakage inhibitor, if Step 2b is used as the step of obtaining a local injection, the second injection precursor can be used immediately before the local injection. By mixing the leakage inhibitor into the body, a local injection with minimal change in action can be obtained.
  • step 2c a local injection is obtained by simultaneously mixing the leakage inhibitor and the active ingredient in the aqueous solvent. Therefore, if step 2c is used as the step of obtaining a local injection, the local injection can be obtained in a shorter time and more easily than in steps 2a and 2b.
  • the local injection according to the present embodiment can be obtained by the production method described above.
  • the local injection suppresses the leakage of the active ingredient from the target site and allows the active ingredient, etc. to remain at the target site. .
  • Example 1 A porcine-derived alkali-treated gelatin hydrolyzate with an isoelectric point of pH 5 (trade name: "Bematrix Gelatin HG", weight-average molecular weight: 4000, manufactured by Nitta Gelatin Co., Ltd.) was used as a leakage inhibitor for Sample 1. .
  • PBS buffer a porcine-derived alkali-treated gelatin hydrolyzate with an isoelectric point of pH 5 (trade name: "Bematrix Gelatin HG", weight-average molecular weight: 4000, manufactured by Nitta Gelatin Co., Ltd.) was used as a leakage inhibitor for Sample 1. .
  • concentrations shown in Table 1 1% by mass, 5% by mass, 10% by mass, 20% by mass, 30% by mass and 40% by mass
  • Various viscosity measurement solutions were obtained, including the first solution.
  • the isoelectric point of the leakage inhibitor of sample 1 was measured by the method described above and found to be 4.65.
  • Example 2 Alkali-treated gelatin hydrolyzate derived from porcine with an isoelectric point of pH 5 (trade name: "Bematrix Gelatin LS-H” manufactured by Nitta Gelatin Co., Ltd.) was heated so that the weight average molecular weight was 650. A gelatin hydrolyzate was obtained by hydrolysis, and this was used as the leakage inhibitor of sample 2. Next, by dissolving the leakage inhibitor in PBS buffer so as to have concentrations shown in Table 1 (10% by mass, 20% by mass, 30% by mass, 40% by mass and 50% by mass), the above-mentioned first solution Various viscometric solutions containing were obtained. The isoelectric point of the leakage inhibitor of Sample 2 was measured by the method described above and found to be 4.02.
  • Example 3 Alkali-treated gelatin hydrolyzate derived from porcine with an isoelectric point of pH 5 (trade name: "Bematrix Gelatin LS-H” manufactured by Nitta Gelatin Co., Ltd.) was heated so that the weight average molecular weight was 20,000. A gelatin hydrolyzate was obtained by hydrolysis, and this was used as the leak inhibitor of sample 3. Then, the leakage inhibitor was heated to 50° C. so as to have concentrations shown in Table 1 (5% by mass, 6% by mass, 7% by mass, 8% by mass, 9% by mass, 10% by mass and 20% by mass). Various viscosity measurement solutions were obtained by dissolving in PBS buffer. The isoelectric point of the leakage inhibitor of sample 3 was measured by the method described above and found to be 4.84.
  • Example 4 Alkali-treated gelatin hydrolyzate derived from porcine with an isoelectric point of pH 5 (trade name: "Bematrix Gelatin LS-H” manufactured by Nitta Gelatin Co., Ltd.) was heated so that the weight average molecular weight was 5,900. A gelatin hydrolyzate was obtained by hydrolysis, and this was used as the leak inhibitor of sample 4. Next, by dissolving the above leakage inhibitor in PBS buffer to each concentration (20% by mass, 30% by mass, and 40% by mass) shown in Table 1, various viscosity measurement solutions including the first solution were obtained. rice field. The isoelectric point of the leak inhibitor of Sample 1 was measured by the method described above and found to be 4.71.
  • sample 21 ⁇ Preparation of sample (local injection)> (Sample 21)
  • Leakage inhibitor weight average molecular weight of gelatin hydrolyzate: 4000
  • concentration shown in Table 2 1% by mass, 5% by mass, 10% by mass, 20% by mass, 30% by mass and 40% by mass
  • PBS buffer aqueous solvent
  • Example 22 Leakage inhibitor of sample 2 prepared in the first test (weight average molecular weight of gelatin hydrolyzate: 650), each concentration shown in Table 2 (10% by mass, 20% by mass, 30% by mass, 40% by mass and 50% by mass) in an aqueous solvent (specifically, PBS buffer) to obtain a topical injection (Sample 22) containing the leakage inhibitor at various concentrations.
  • aqueous solvent specifically, PBS buffer
  • Example 23 Leakage inhibitor (weight average molecular weight of gelatin hydrolyzate: 20000) of sample 3 prepared in the first test was added to each concentration shown in Table 2 (5% by mass, 6% by mass, 7% by mass, 8% by mass, 9% by mass and 10% by mass), and dispersed in an aqueous solvent (specifically, PBS buffer) to obtain a dispersion, and the dispersion is dissolved by heating to 50 ° C. to suppress leakage. A topical injection (Sample 23) containing the agent at various concentrations was obtained.
  • an aqueous solvent specifically, PBS buffer
  • Example 2A Glycerin (reagent special grade, manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.) was added to an aqueous solvent (specifically, PBS buffer) so that each concentration shown in Table 2 (10% by mass, 40% by mass, and 50% by mass). to obtain local injections (Sample 2A) containing glycerin at various concentrations.
  • the mass of the filter paper that absorbed the local injection that leaked from the puncture site was measured, and the leakage rate of the local injection that leaked from the puncture site (%, the mass of the local injection that leaked from the puncture site / 0.2 g ⁇ 100 ) was calculated.
  • the leakage rate was 9.0% or less, the local injection was evaluated as having suppressed leakage from the target site.
  • Table 2 shows the results. In Table 2, for example, the leakage rate (%) of the local injection containing 10% by mass of the leakage inhibitor in Sample 21 is shown where the row of Sample 21 and the column of 10% by mass overlap. That is, according to this test, the leakage rate (%) of the local injection containing 10% by mass of the leakage inhibitor in Sample 21 was 7.0%.
  • Sample 21 has a leakage rate of 9.0% or less in a local injection containing 10 to 30% by mass of a leakage inhibitor
  • Sample 22 is a local injection containing 30 to 40% by mass of a leakage inhibitor.
  • the above leakage rate was 9.0% or less in the injection, suggesting that each of them has a good leakage suppressing effect.
  • the leakage rate was 9.0% or less in a local injection containing 7 to 8% by mass of a leakage inhibitor, but the local injection was made from gelatin hydrolyzate with a weight average molecular weight of 20000. Since this leakage inhibitor is used, it is necessary to heat it to 50° C. for sol formation. Therefore, it was judged that the implementation of the local injection was not practical and inappropriate.
  • Sample 2A had a leakage rate of 9.0% or less in a local injection containing 40 to 50% by mass of glycerin. It was deemed unsuitable because it was impractical to implement the agent.
  • sample 31 Leakage inhibitor (weight average molecular weight of gelatin hydrolyzate: 4000) of sample 1 prepared in the first test was added to each concentration shown in Table 3 (1% by mass, 5% by mass, 10% by mass, 20% by mass, 30% by mass and 40% by mass) were dissolved in an aqueous solvent (specifically, PBS buffer) to obtain local injections (Sample 31) containing the leakage inhibitor at various concentrations.
  • an aqueous solvent specifically, PBS buffer
  • Example 3A Glycerin (reagent special grade, manufactured by FUJIFILM Wako Pure Chemical Industries, Ltd.) was added to an aqueous solvent (specifically, PBS buffer) at each concentration shown in Table 3 (10% by mass, 40% by mass, and 50% by mass). to obtain local injections (Sample 3A) containing glycerin at various concentrations.
  • ⁇ Leakage suppression test> Syringes (manufactured by Terumo Corporation) equipped with injection needles having an outer diameter of 23G are each filled with 1 mL of the various topical injections of Sample 31 and Sample 3A described above, and the syringes are injected into the subject to be injected. By doing so, 0.2 mL (equivalent to 0.2 g) of the local injection was injected into the subject to be injected. Thereafter, a commercially available filter paper (manufactured by Advantech) cut into 1 cm squares in the same manner as in the second test was allowed to absorb the local injection that leaked from the puncture site, and the mass of the filter paper was measured to determine whether the leaked product leaked from the puncture site. The leakage rate (%) of the local injection was calculated.
  • Sample 31 has a leakage rate of 11.0% or less in a local injection containing 30 to 40% by mass of a leakage inhibitor, suggesting that it has a good leakage inhibition effect.
  • Sample 3A showed a leakage rate exceeding 11.0% in various local injections containing glycerin at a predetermined concentration.
  • sample 41 ⁇ Preparation of sample (local injection)> (Sample 41)
  • Leakage inhibitor weight average molecular weight of gelatin hydrolyzate: 4000
  • concentration shown in Table 4 1% by mass, 5% by mass, 10% by mass, 20% by mass, 30% by mass and 40% by mass
  • PBS buffer aqueous solvent
  • a syringe manufactured by Terumo Corporation equipped with a syringe needle having an outer diameter of 25G is filled with 1 mL of the above-described local injection of sample 41, and the syringe is injected into the above-described subject to be injected.
  • 0.2 mL (equivalent to 0.2 g) of the local injection was injected into the subject to be injected.
  • a commercially available filter paper manufactured by Advantech
  • Sample 41 had a leakage rate of 8.0% or less in a local injection containing 20 to 40% by mass of a leakage inhibitor, suggesting that it has a good leakage inhibition effect.
  • sample 51 ⁇ Preparation of sample (local injection)> (Sample 51)
  • Leakage inhibitor weight average molecular weight of gelatin hydrolyzate: 4000
  • concentration shown in Table 5 1% by mass, 3% by mass, 5% by mass, 7.5% by mass %, 10% by mass, 15% by mass and 20% by mass
  • PBS buffer aqueous solvent
  • Sample 51 has a leakage rate of 2.5% or less in a local injection containing 7.5 to 10% by mass of a leakage inhibitor, suggesting that it has a good leakage inhibition effect.
  • sample 61 ⁇ Preparation of sample (local injection)> (Sample 61)
  • Leakage inhibitor weight average molecular weight of gelatin hydrolyzate: 4000
  • concentration shown in Table 6 1% by mass, 3% by mass, 5% by mass, 7.5% by mass % and 10% by mass
  • Sample 61 has a leakage rate of 1.0% or less in a local injection containing 5.0 to 7.5% by mass of a leakage inhibitor, suggesting that it has a good leakage suppression effect. rice field.
  • a cell suspension was prepared by dispersing normal human fibroblasts (manufactured by Kurashiki Boseki Co., Ltd.) in a PBS buffer in a plastic container at 5.0 ⁇ 10 5 cells/mL.
  • sample 71 ⁇ Preparation of sample (local injection)> (Sample 71)
  • the leakage inhibitor of sample 1 prepared in the first test weight average molecular weight of gelatin hydrolyzate: 4000
  • the leakage inhibitor of sample 1 prepared in the first test was added so that the final concentration of sample 1 was 20% by mass. and uniformly dispersing the cells in the plastic container to prepare a local injection (Sample 71) having a final cell concentration of 2.5 ⁇ 10 5 cells/mL.
  • sample 73 To the cell suspension in the plastic container, the leakage inhibitor of sample 3 prepared in the first test (weight average molecular weight of gelatin hydrolyzate: 20000) was added to the final concentration of sample 3 to 8.0% by mass. A local injection with a final cell concentration of 2.5 ⁇ 10 5 cells/mL ( Sample 73) was prepared.
  • Example 7A By further adding a PBS buffer to the cell suspension in the plastic container and dispersing the cells uniformly in the plastic container, the final cell concentration was 2.5 ⁇ 10 5 cells/mL. A topical injection (Sample 7A) was prepared.
  • ⁇ Cell retention test> The absorbance at a wavelength of 600 nm of the local injections of Samples 71, 73 and 7A described above was measured using an absorbance meter (manufactured by Thermo Fisher Scientific). Specifically, the absorbance at a wavelength of 600 nm of each sample at 0, 2, 4, 6, 8 and 10 minutes after preparation was examined with the above-mentioned absorbance meter. For the local injection of each sample, the absorbance measured at 0 minutes after preparation was regarded as 100% cell retention, and the cell retention was calculated from the absorbance measured at each time point.
  • the cell retention rate is an index representing how uniformly cells are dispersed in the local injection. The absorbance decreases to such an extent that the cells are not evenly dispersed in the local injection due to sedimentation or the like. Therefore, the lower the absorbance, the lower the cell retention rate. Table 7 shows the results.
  • Samples 71 and 73 maintain better cell retention rates than Sample 7A, suggesting that they have excellent cell retention. Therefore, since the local injections of Samples 71 and 73 have excellent cell retention properties, it is considered that they can efficiently deliver the cells, which are the active ingredient, to the target site.
  • the topical injection of Sample 73 needs to be prepared by heating to 50° C. for solification using a leak inhibitor consisting of a gelatin hydrolyzate with a weight-average molecular weight of 20,000. was deemed inappropriate as it was impractical.
  • sample 81 A local injection (Sample 81) was prepared in the same manner as the local injection of Sample 71 prepared in the seventh test, with a leakage inhibitor (weight average molecular weight of gelatin hydrolyzate: 4000) having a concentration of 20% by mass. prepared.
  • Example 83 Local injection (Sample 83 ) was prepared.
  • Example 8A A topical injection (Sample 8A) was prepared by uniformly dispersing the cells in a plastic container in the same manner as the topical injection of Sample 7A prepared in the seventh test.
  • ⁇ Cell ejection test> A cell ejection test was performed on Samples 81, 83 and 8A using the following method. That is, 3 mL of the local injections of Sample 81, Sample 83, and Sample 8A described above were each aspirated using a syringe (manufactured by Terumo Corporation) equipped with an injection needle having an outer diameter of 27 G, and immediately after aspiration and after aspiration. The local injection was discharged from the syringe into a plastic container after 10 minutes had passed. Subsequently, in the plastic container containing the topical injection, the absorbance of each sample at a wavelength of 600 nm was examined with the same absorbance meter as used in the fifth test.
  • the absorbance measured in the local injection filled in the plastic container without being aspirated with the syringe is regarded as 100% cell ejection rate, and the cell ejection rate is calculated from the absorbance measured in the plastic container of each sample was calculated.
  • the cell ejection rate means an index representing how many cells are ejected to the outside after appropriately passing through the injection needle.
  • the absorbance decreases because the density of the cells in the plastic container is so low that the cells do not properly pass through the injection needle and are expelled to the outside. Therefore, the lower the absorbance, the lower the cell ejection rate.
  • Table 8 shows the results. In Table 8, a topical injection filled in a plastic container without being aspirated with the syringe is shown as "Control".
  • samples 81 and 83 have excellent cell ejection properties because the cell ejection rate is maintained better than that of sample 8A. Therefore, since the local injections of Samples 81 and 83 have excellent cell-ejecting properties, it is considered that cells, which are the active ingredient, can be efficiently delivered to the target site.
  • the topical injection of Sample 83 needs to be prepared by heating to 50° C. for solification using a leak inhibitor consisting of a gelatin hydrolyzate with a weight-average molecular weight of 20,000. was deemed unsuitable because it was impractical and there was concern about damage to the cells.

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Abstract

L'invention concerne un agent d'inhibition de fuite comprenant un hydrolysat de gélatine ayant un poids moléculaire moyen en poids de 5000 ou moins, la viscosité, à 25 °C, d'une première solution, obtenue par dissolution de l'hydrolysat de gélatine dans une solution saline tamponnée au phosphate de telle sorte que la concentration de l'hydrolysat de gélatine atteigne 40 % en masse, étant de 20 mPa·s ou moins.
PCT/JP2022/032793 2021-11-16 2022-08-31 Agent d'inhibition de fuite pour substance d'injection locale, substance d'injection locale le contenant, et procédé de production d'une substance d'injection locale WO2023089906A1 (fr)

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CA3220517A CA3220517A1 (fr) 2021-11-16 2022-08-31 Agent d'inhibition de fuite pour substance d'injection locale, substance d'injection locale le contenant, et procede de production d'une substance d'injection locale
KR1020247003686A KR20240095404A (ko) 2021-11-16 2022-08-31 국소 주사제용의 누출 억제제, 이를 포함하는 국소 주사제, 및 국소 주사제의 제조 방법
CN202280067824.3A CN118119407A (zh) 2021-11-16 2022-08-31 局部注射剂用的渗漏抑制剂、包含该渗漏抑制剂的局部注射剂以及局部注射剂的制造方法

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